The major objective of this project is to further define the role of major histocompatibility complex (MHC) antigens in immunocompetent cell interactions and their involvement in the immunogenic association with exogenous antigens. The proposed research is directed toward understanding the nature of T lymphocyte recognition of macrophage-associated antigens and involves a combination of cellular immunological and peptide chemistry approaches. The rationale is that by first defining the exogenous antigenic determinants for T cell responsiveness using small synthetic peptide antigens, we may be able to characterize the immunogenic complex presented by macrophages and the antigen recognition process of T cells. Using this approach we will investigate: 1) the critical amino acids of small peptide antigens that are directly recognized by T cells and macrophages; 2) macrophage and T cell structures that specifically bind antigenic determinants of peptide fragments; 3) how macrophages process small peptides to create the immunogenic moiety and the role of macrophage degradation of large proteins to immunogenic fragments; 4) the mechanisms of genetic regulation of immune responsiveness (Ir gene function) to small peptide antigens and the cellular interactions influencing responsiveness; and 5) the relationship between I region-associated (Ia) antigen expression and Ir gene function. The results of these studies should contribute to an understanding of the signals required for lymphocyte activation by elucidating MHC gene product interactions with exogenous antigens and their role in immunocompetent cell interactions.